Dysport

CLINICAL PHARMACOLOGY

Mechanism of Action

Dysport inhibits release of the
neurotransmitter, acetylcholine, from peripheral cholinergic nerve endings.
Toxin activity occurs in the following sequence: Toxin heavy chain mediated
binding to specific surface receptors on nerve endings, internalization of the
toxin by receptor mediated endocytosis, pH-induced translocation of the toxin
light chain to the cell cytosol and cleavage of SNAP25 leading to intracellular
blockage of neurotransmitter exocytosis into the neuromuscular junction. This
accounts for the therapeutic utility of the toxin in diseases characterized by
excessive efferent activity in motor nerves.

Recovery of transmission occurs
gradually as the neuromuscular junction recovers from SNAP25 cleavage and as
new nerve endings are formed.

Pharmacodynamics

The primary pharmacodynamic effect
of Dysport is due to chemical denervation of the treated muscle resulting in a
measurable decrease of the compound muscle action potential, causing a
localized reduction of muscle activity.

Pharmacokinetics

Using currently available
analytical technology, it is not possible to detect Dysport in the peripheral
blood following intramuscular injection at the recommended doses.

Clinical Studies

Cervical Dystonia

The efficacy of Dysport was
evaluated in two well-controlled, randomized, double-blind, placebo controlled,
single dose, parallel group studies in treatment-na´ve cervical dystonia
patients. The principal analyses from these trials provide the primary
demonstration of efficacy involving 252 patients (121 on Dysport, 131 on
placebo) with 36% male and 64% female. Ninety-nine percent of the patients were
Caucasian.

In both placebo controlled studies
(Study 1 and Study 2), a dose of 500 Units Dysport was given by intramuscular
injection divided among two to four affected muscles. These studies were
followed by long-term open label extensions that allowed titration in 250 Unit
steps to doses in a range of 250 to 1000 Units, after the initial dose of 500
Units. In the extension studies, re-treatment was determined by clinical need
after a minimum of 12 weeks. The median time to re-treatment was 14 weeks and
18 weeks for the 75th percentile.

The primary assessment of efficacy
was based on the total Toronto Western Spasmodic Torticollis Rating Scale
(TWSTRS) change from baseline at Week 4 for both studies. The scale evaluates
the severity of dystonia, patient perceived disability from dystonia, and pain.
The adjusted mean change from baseline in the TWSTRS total score was
statistically significantly greater for the Dysport group than the placebo
group at Weeks 4 in both studies (see Table 4).

Analyses by gender, weight,
geographic region, underlying pain, cervical dystonia severity at baseline and
history of treatment with botulinum toxin did not show any meaningful
differences between groups.

Table 5 indicates the average
Dysport dose, and percentage of total dose, injected into specific muscles in
the pivotal clinical trials.

a Total number of patients in combined studies 2
and 1 who received initial treatment=121.

Glabellar Lines

Three double-blind, randomized,
placebo-controlled, clinical studies evaluated the efficacy of Dysport for use
in the temporary improvement of the appearance of moderate to severe glabellar
lines. These three studies enrolled healthy adults (ages 19-75) with glabellar
lines of at least moderate severity at maximum frown. Subjects were excluded if
they had marked ptosis, deep dermal scarring, or a substantial inability to
lessen glabellar lines, even by physically spreading them apart. The subjects
in these studies received either Dysport or placebo. The total dose was
delivered in equally divided aliquots to specified injection sites (see Figure
1).

Overall treatment success was
defined as post-treatment glabellar line severity of none or mild with at least
2 grade improvement from Baseline for the combined investigator and subject
assessments (composite assessment) on Day 30 (see Table 6). Additional
endpoints for each of the studies were post-treatment glabellar line severity
of none or mild with at least a 1 grade improvement from Baseline for the
separate investigator and subject assessments on Day 30.

After completion of the randomized
studies, subjects were offered participation in a two-year, open-label
re-treatment study to assess the safety of multiple treatments.

Table 6: Treatment Success at
Day 30 (None or Mild with at least 2 Grade Improvement from Baseline at Maximum
Frown for the combined Investigator and Subject Assessments (Composite))

Study

2 Grade Improvement

Dysport
n/N (%)

Placebo
n/N (%)

GL-1

58/105 (55%)

0/53 (0%)

GL-2

37/71 (52%)

0/71 (0%)

GL-3

120/200 (60%)

0/100 (0%)

Treatment with Dysport reduced the
severity of glabellar lines for up to four months.

Study GL-1

Study GL-1 was a single dose,
double-blind, multi-center, randomized, placebo-controlled study in which 158
previously untreated subjects received either placebo or 50 Units of Dysport,
administered in five aliquots of 10 Units (see Figure 1). Subjects were
followed for 180 days. The mean age was 43 years; most of the subjects were
women (85%), and predominantly Caucasian (49%) or Hispanic (47%). At Day 30,
55% of Dysport-treated subjects achieved treatment success: a composite 2 grade
improvement of glabellar line severity at maximum frown (see Table 6).

In study GL-1, the reduction of
glabellar line severity at maximum frown was greater at Day 30 in the Dysport
group compared to the placebo group as assessed by both Investigators and
subjects (see Table 7).

Table 7: GL-1: Investigator's
and Subject's Assessment of Glabellar Line Severity at Maximum Frown Using a
4-point Scale (% and Number of Subjects with Severity of None or Mild)

Investigator's Assessment

Subject's Assessment

Dysport
N=105

Placebo
N=53

Dysport
N=105

Placebo
N=53

14

90% 95

17%9

77% 81

9% 5

30

88% 92

4%2

74% 78

9% 5

60

64% 67

2%1

60% 63

6% 3

90

43% 45

6%3

36% 38

6% 3

120

23% 24

4% 2

19% 20

6% 3

150

9% 9

2% 1

8% 8

4% 2

180

6% 6

0% 0

7% 7

8% 4

Study GL-2

Study GL-2 was a repeat dose,
double-blind, multi-center, placebo-controlled, randomized study. The study was
initiated with two or three open-label treatment cycles of 50 Units of Dysport
administered in five aliquots of 10 Units Dysport (see Figure 1). After the
open-label treatments, subjects were randomized to receive either placebo or 50
Units of Dysport. Subjects could have received up to four treatments through
the course of the study. Efficacy was assessed in the final randomized
treatment cycle. The study enrolled 311 subjects into the first treatment cycle
and 142 subjects were randomized into the final treatment cycle. Overall, the
mean age was 47 years; most of the subjects were women (86%) and predominantly
Caucasian (80%).

The proportion of responders in
the final treatment cycle was comparable to the proportion of responders in all
prior treatment cycles.

After the final repeat treatment
with Dysport, the reduction of glabellar line severity at maximum frown was
greater at Day 30 in the Dysport group compared to the placebo group as
assessed by both Investigators and subjects (see Table 8).

Table 8: GL-2: Investigator's
and Subject's Assessments of Glabellar Line Severity at Maximum Frown Using a
4-point Scale (% and Number of Subjects with Severity of None or Mild)

Investigator's Assessment

Subject's Assessment

Dysport
N=71

Placebo
N=71

Dysport
N=71

Placebo
N=71

30

85% 60

4% 3

79% 56

1% 1

Study GL-3

Study GL-3 was a single dose,
double-blind, multi-center, randomized, placebo-controlled study in which 300
previously untreated subjects received either placebo or 50 Units of Dysport,
administered in five aliquots of 10 Units (see Figure 1). Subjects were
followed for 150 days. The mean age was 44 years; most of the subjects were
women (87%), and predominantly Caucasian (75%) or Hispanic (18%).

In study GL-3, the reduction of
glabellar line severity at maximum frown was greater at Day 30 in the Dysport
group compared to the placebo group as assessed by both Investigators and
subjects (see Table 9).

Table 9: GL-3: Investigator's
and Subject's Assessment of Glabellar Line Severity at Maximum Frown Using a
4-point Scale (% and Number of Subjects with Severity of None or Mild)

Investigator's Assessment

Subject's Assessment

Dysport
N=200

Placebo
N=100

Dysport
N=200

Placebo
N=100

14

83% 166

5% 5

83% 165

2% 2

30

86% 171

0% 0

82% 163

2% 2

60

75% 150

1%1

65% 130

4% 4

90

51%102

1% 1

46%91

2% 2

120

29% 58

1% 1

31% 61

3% 3

150

16% 32

1% 1

16% 31

3% 3

Geriatric Subjects

In GL1, GL2, and GL3, there were 8
subjects aged 65 and older who were randomized to Dysport 50 Units in 5 equal
aliquots of 10 Units (4) or placebo (4). None of the geriatric Dysport subjects
were a treatment success at maximum frown at Day 30.

Last reviewed on RxList: 5/31/2012
This monograph has been modified to include the generic and brand name in many instances.